CN102292049B

CN102292049B - Apparatus for transportation of oxygen to implanted cells

Info

Publication number: CN102292049B
Application number: CN200980155498.6A
Authority: CN
Inventors: Y·斯特恩; U·巴尔卡伊; A·罗特姆; M·赖因格沃茨; Y·罗兹
Original assignee: Beta O2 Technologies Ltd
Current assignee: Beta O2 Technologies Ltd
Priority date: 2008-11-26
Filing date: 2009-11-25
Publication date: 2015-04-15
Anticipated expiration: 2029-11-25
Also published as: EP2370021A4; EP2370021A2; AU2009321193A1; WO2010061387A2; ES2650496T3; CA2744643C; WO2010061387A3; US8043271B2; DK2370021T3; US20100130916A1; AU2009321193B2; CA2744643A1; CN102292049A; EP2370021B1

Abstract

Apparatus is provided which includes a housing (24), configured for insertion into a body of a subject. The apparatus includes functional cells (32) coupled to the housing (24) and a source of oxygen configured to supply oxygen to the functional cells. The apparatus further includes an oxygen delivery interface (27) configured to receive oxygen from the source of oxygen, and to facilitate passage of the oxygen to the functional cells (32), while the housing (24) is disposed within the body of the subject. Other applications are also described.

Description

To the equipment of transplanted cells transport oxygen

Cross-reference to related applications

The application:

A () is the part continuation application being entitled as the PCT patent application PCT/IL08/001204 of " Air gap forsupporting cells " submitted to for 7th in JIUYUE in 2008 of Stern and Rozy, it requires the priority being entitled as the U.S. Provisional Patent Application 60/993,052 of Rozy and Stern of " Air gap for supporting cells " in JIUYUE in 2007 submission on the 7th; And

B () is the U.S. Patent application 12/315 being entitled as the people such as the Stern of " Apparatus for transportation ofoxygen to implanted cells " submitted on November 26th, 2008, the part continuation application of 102, and advocate its priority.

More than application is all incorporated to herein by quoting.

Technical field

Application more of the present invention briefly relate to implantable medical apparatus.Particularly, application more of the present invention relate to generation oxygen and provide the implantable device of oxygen to the cell transplanted (cell as in the islets of langerhans of transplanting).

Background technology

Oxygen to include oxygen metabolism interior much physiology and metabolic process indispensable.The confession hypoxgia of transplanted cells often causes cell injury or death.Oxygen supply is vital factor maintaining in the cell transplanted.

In the individuality of health, regulate insulin releasing, with the scope making blood sugar level be maintained at about 70-110 milligram/decilitre.In diabetics, do not produce insulin (type i diabetes), or soma makes unsuitable reaction (type ii diabetes) to the insulin produced.Its result increases blood sugar level.

Due to graft-host rejection, and to the ischemic condition that graft produces for hypoxgia, and undermine the success of many cell transplantations.After implanting cell, from bodily tissue, in some cases, from by means of the plastidogenetic blood vessel structure of angiogenesis factor such as VEGF and bFGF around transplanting, to the cell oxygen supply of implanting (mainly through diffusion).But natural diffusion velocity is too slow, can not provide the oxygen of considerable aequum to cell.

The PCT of the people such as Vardi discloses WO 01/50983 and enters the U.S. Patent application 10/466 of thenational phase, 069 (being incorporated to herein by quoting), describe implantable device, it comprises the room of accommodation function sexual cell and the Oxygen Generator to described functional cell oxygen supply.In one embodiment, when described Oxygen Generator is described to be included in illuminated, carbon dioxide transitions is become the photosynthetic cells of oxygen.In another embodiment, described Oxygen Generator is described to comprise the electrode being produced oxygen by electrolysis.

The U.S. Patent Application Publication 2005/0136092 (being incorporated to herein by quoting) of Rotem describes the equipment comprising and be suitable for the room of implanting in individual health, and described room comprises functional cell and contains chlorophyllous element (it comprises the chlorophyll of obligate photoautotroph).Typically, describedly complete photosynthetic cells and/or the chloroplast of separation is comprised containing chlorophyllous element.Described containing chlorophyllous element to described functional cell oxygen supply, and/or consume described functional cell produce carbon dioxide.Described room has one or more surfaces wall, and described wall can osmotrophy thing and described cell produces or the material of secretion through overregulating.The composition of the immunity described cell of isolation and health typically gone back by described wall.Under described room is adapted to implant the skin of described object, or in peritoneum.Described equipment also comprises and is adapted to provide the light source of illumination to described containing chlorophyllous element.Described room can comprise oxygen sensor, and it detects the vicinity at described functional cell, and/or at the described oxygen concentration containing the vicinity of chlorophyllous element.There is provided a series of pulsed light usually to reduce the power consumption of described equipment, and/or provide the described control containing chlorophyllous element oxygen-producing amount, and/or provide the described control containing chlorophyllous components consume amount of carbon dioxide.In some embodiments of the present invention, described room comprises oxygen bin, and it typically comprises the material such as storing and discharge oxygen in response to the oxygen concentration near described oxygen bin.Described oxygen bin typically store by described produce containing chlorophyllous element exceed described functional cell oxygen required at present, and if the described hypoxgia produced containing chlorophyllous element afterwards, discharge the oxygen of storage.

The open WO 06/059322 of PCT of the people such as Evron describes equipment, and it comprises the room being suitable for implanting individual health.Described room comprises functional cell and contains chlorophyllous element (it comprises the chlorophyll of obligate photoautotroph).Also describe other embodiments.

The United States Patent (USP) 5,713,888 authorizing the people such as Neuenfeldt describes the implant assembly for host tissue.Described implant assembly comprises satchel, and described satchel comprises the wall member of the room defined for holding the second element.Described wall member comprises outer vascularization film (outer vascularizing membrane), and the structure of described outer vascularization film causes blood vessel structure near described host tissue, the neighbouring growth at the interface between described vascularization film and host tissue.Described assembly comprises the second element, and it is inserted in described room movably, and described room comprises the inside for receiving cell and defines the wall member of immuncexclusion (it isolates described cell from the immunoreation of described host tissue).

The United States Patent (USP) 6,368,592 authorizing the people such as Colton describes and is used for by being become by water electrolysis the Oxygen Generator of oxygen and hydrogen to produce technology to cell oxygen supply in the external or body of oxygen.Described Oxygen Generator is described to cell oxygen supply, and described cell is included in the closed chamber for implanting in health, such as, by the immuno separation room that the semi permeability screen layer of the component entering and leave described room can be selected to define.

The United States Patent (USP) 6,960,351 authorizing the people such as Dionne describes for implanting the immune isolation carrier in the individuality of cell, and described cell produces the product of needs or provides required metabolic function.Described carrier comprises, center containing isolated cell, with be enough to the material maintaining described cell, and the biocompatible perimeter region of permselective property not containing described isolated cell, its described center of immunity isolation is also sent the product of secretion to described individuality or provides metabolic function.Described carrier is described to be particularly suitable for the islets of langerhans insulin delivery from being isolated by immunity, and is advantageously used in the product sending high molecular, such as, be greater than the product of IgG.Also describe the method preparing the implantable carrier of the immune isolation of biocompatibility, comprise the first embodiment of coextrusion operation, and the second embodiment of separate operations.Describe a kind of method, it is for being isolated in cell in the implantable carrier of biocompatibility immunity isolation, and described carrier protects segregate cell from the immune system attack in the individuality of implanted described carrier.Describe and provide required biologic or the method for metabolic function to individuality, it comprises implants described individuality by immune isolation carrier, and described immunity isolation carrier contains the cell of the isolation producing described product or provide described metabolic function.

This ' 351 patents describe a kind of carrier, at least in one aspect, its can make any isolated cell intracardiac in described fully close to the surrounding tissue (comprising the blood flow of described receptor) of receptor to maintain vitality and the function of described isolated cell.But, be not only ascribe its structural limitations in all situations for the formation of the diffusibility limitation of the material of described carrier.Can use some additive, it changes or improves the diffusibility of underlying carrier, or the transhipment of nutrient or oxygen.Such as, interior media can be supplemented with oxygen-saturated perfluorocarbon compound, lowers the needs of the oxygen close contact carried with blood thus.This is described to enable the cell or tissue of isolation to sustain life power, and meanwhile, such as, angiotensin is released into surrounding tissue from described carrier gradient, stimulates capillary ingrowth.

Authorize Clark, Jr. the United States Patent (USP) 4 of people is waited, 721,677 describe implantable biosensor, and detect the method analyzing the product (such as hydrogen peroxide) that the enzyme reaction between thing (as glucose) and enzyme produces in the presence of oxygen.Described biosensor is described to be configured with the closed chamber holding oxygen, and can transform and extract oxygen for the animal tissue adjacent from container.Described biosensor design is used for the product by the thing function that performs an analysis produced by optics or electrical method detection of enzymatic reactions.

About the document of perfluorocarbon compound and using method at Faithful, N.S.Anaesthesia, 42, pp.234-242 (1987) and NASA Tech Briefs MSC-21480, state in U.S.Govt.PrintingOffice, Washington, D.C.20402.

The U.S. Patent Application Publication 2005/0025680 of the people such as Monzyk describes photodissociation cell and implants the photodissociation artificial lung of described cell.Water is changed into oxygen for blood absorption by described photodissociation artificial lung, regulates pH, removing carbon dioxide, and produces electric energy simultaneously.Described photodissociation artificial lung comprises photodissociation cell, and all chemical reactions occur in described photodissociation cell.In addition, Monzyk describes the photodissociation sensitive material for generation of oxygen.These materials are used for the making of gasless artificial lung.Described photodissociation cell is described for guiding the chemical reaction in other organs except lung, and for maintaining the breathe air in closed system.

Following patent and patent application may be relevant:

The open WO 01/050983 of PCT of Vardi

The open WO 07/138590 of PCT of Gross

The open WO 08/062417 of PCT of Rotem

The open WO 08/065660 of PCT of Rotem

The open WO 09/031154 of PCT of Stem

Authorize the United States Patent (USP) 2,564,977 of Hu

Authorize the United States Patent (USP) 5,614,378 of the people such as Yang

Authorize the United States Patent (USP) 6,268,161 of the people such as Han

Authorize the United States Patent (USP) 6,383,478 of the people such as Prokop

Authorize the United States Patent (USP) 6,630,154 of the people such as Fraker

Authorize Clark, the United States Patent (USP) 6,815,186 of the people such as Jr.

The U.S. Patent Application Publication 2003/0113302 of the people such as Revazova

The U.S. Patent Application Publication 2004/0133188 of Vardi

The U.S. Patent Application Publication 2004/0178358 of Kreiss

The U.S. Patent Application Publication 2006/0024276 of the people such as Ricordi

The U.S. Patent Application Publication 2006/0035370 of Lee

The U.S. Patent Application Publication 2009/0012502 of Rotem

Following article may be relevant:

The people such as Kaisers U, " Liquid ventilation, " British Journal of Anaesthesia91 (1): 143-151 (2003)

The people such as Lacy PE, " Maintenance of normoglycemia in diabetic mice bysubcutaneous xenografts of encapsulated islets, " Science 1782-4 (1991)

The people such as Lorch H, " Central Venous Access Ports Placed by InterventionalRadiologists:Experience with 125 Consecutive Patients; " JournalCardio Vascular and Interventional Radiology, 180-184 page, Issue Volume 24, Number 3 (2001)

The people such as Silva AI, " An overview on the development of a bio-artificialpancreas as a treatment of insulin-dependent diabetes mellitus, " Med Res Rev26 (2): 181-222 (2006)

Waschke KF and Frietsch T, " Modified haemoglobins and perfluorocarbons " (Current Opinion in Anaesthesiology.12 (2): 195-202 (1999).

Summary of the invention

In application more of the present invention, disclose a kind of equipment, it comprises the shell of the cell for holding transplanting, and it is designed in the health of subcutaneous implantation object.The cell of described transplanting typically comprises functional cell, such as, be arranged in the cell of Langerhan's cells, and in this case typically in islets of langerhans.Described functional cell is typically arranged in liquid or gel layer.Described shell comprises oxygen and sends interface (such as transparent surface, one or more valve or one or more pipe), and it promotes that oxygen is to described cell traffic.Described equipment comprises oxygen source, or oxygen supply (such as comprising air, other mixture of gas or the container of pure oxygen), and it is connected with described shell by described interface.According to the interval of regulation, such as, every several hours or every several weeks, typically, at least one times/week, described oxygen source is connected with described interface by described object, and described oxygen source is to the oxygen of described shell supply limited amount.

In some applications, described oxygen source comprises container, and it accommodates the multiple gases comprising oxygen.Described gas is positioned at described container and pressure is 1atm or higher.Typically, described oxygen source comprises about 5% carbon dioxide to remain on the balance of gas concentration lwevel between described enclosure and outside.For some application, described oxygen source comprises liquid, before described liquid is included in and described vector injection entered described shell, the oxygen carrier of oxygenation (such as, based on the oxygen carrier of hemoglobin, such as, the hemoglobin of chemical modification, or " microvesicle " (it comprises fluorocarbon such as R-4112, perfluorodecalin or other perfluorochemicals)).

Typically, described shell comprises oxygen bin, and its function is the pipeline as oxygen diffusion, and feeds to the excessive oxygen of described shell for storing described oxygen source as bin.In some applications, described oxygen bin comprises gas container, and it is the gas zones comprising oxygen and carbon dioxide in described shell.In some applications, described oxygen bin comprises the oxygen carrier based on liquid.In this type of application, the function of described oxygen carrier stores when oxygen excess or transhipment oxygen, and discharge oxygen when aerobic.

For some application, described shell comprises multiple thrust, its ground of center radiation shape from described shell projection.Described oxygen carrier is typically stored in described thrust, and it improves the surface area absorbing oxygen from the vascular system around described shell.The oxygen absorbed by described thrust is stored in the housing by described oxygen carrier.

Typically, the size that the volume of the oxygen provided to described shell and concentration depend on described shell and the functional cell number be positioned at wherein.In addition, the composition of the oxygen carrier injecting described shell is depended on to the oxygen-supplying amount of described shell.That is, with the fluid-phase ratio of same volume comprising free oxygen, the time that the fluid comprising the certain volume of preliminary filling oxygen carrier can make the functional cell in described shell remain longer.Usually, described oxygen send interface promote constantly to described functional cell to be enough to meet described functional cell in the volume of little keto consumpting speed in 2 weeks of specific time such as 12 and concentration oxygen supply.

In some applications, described oxygen sends the surface that interface comprises described shell, and it comprises the material that can pierce through, such as rubber, organosilicon or plastics, and can enter the inside of described shell after piercing through described surface.In this type of application, described oxygen source is connected with device (such as pin), and the oxygen that described device transdermally enters described shell sends interface.For in the application that wherein said oxygen source is connected with pin, the skin of object described in described needle-penetration, then pierces through the surface of described shell.

Be positioned at the fluid of the low oxygen content of described shell from being wherein removed, simultaneously to the fluid of described shell supply elevated oxygen level.(note, in the scope of " fluid ", comprise liquids and gases).In some applications, described pin comprises the two chamber pin having input room and export room.By described input room (such as by the syringe of user operation routine, or passing through electric mechanism), the fluid of elevated oxygen level is injected in described shell on one's own initiative.Inject simultaneously with described, owing to injecting the fluid of described elevated oxygen level, in described shell, introduce pressure, thus, the fluid being positioned at described shell is extracted out from described shell passively by described output room.

In some applications, described pin comprises single chamber formula pin, and described oxygen source comprises the syringe be connected with pump.Before described cell oxygen supply, described syringe is connected with described pin, shell described in described needle-penetration, and described pump is by the fluid of described syringe from the low oxygen content of pumping unit in described shell.Then the fluid injecting of the part elevated oxygen level in described syringe is entered in described shell.In this type of application, described pump promotes that (a) initiatively supplements the circulation of described fluid from withdrawn fluid in described shell and (b).In some applications, when not having pump, user implements this circulation.

In some applications, described shell and one or more open fluid communication, described opening respectively comprises transparent surface, and it is convenient to the inside being entered described shell by pin.Described opening contacts with the subcutaneous tissue of described object.In some applications, described opening is connected directly to the surface of the shell contacted with subcutaneous tissue.Or described opening is positioned at a distance relative to described shell, and is connected by each Guan Yuqi.

In some applications, described shell with enter fluid hose and go out fluid hose (they the first end be positioned at described shell) separately fluid and be communicated with.Described input pipe and outlet tube the second end is separately positioned at the outside of described subject's body.Typically, the end being positioned at the input pipe of described subject's body outside is used as described oxygen and sends interface.Oxygen from described oxygen source to be injected in described shell with fluid replacement and the oxygen concentration improved in described shell by described input pipe.With the while of being entered by described fluid active infusion in described shell, the fluid being positioned at described shell discharges described shell passively by described outlet tube, or is extracted from described shell on one's own initiative by the suction source be connected with described outlet tube.

In some applications, described shell is pliable and tough, and near the thoracic cavity of implanted described object.In this type of application, in response to the natural motion in thoracic cavity, described pliable sheath moves, thus described oxygen containing fluid in described shell initiatively and transport continuously.

In application more of the present invention, described equipment comprises the shell accommodating described functional cell, and described shell is by near the trachea of the described object of subcutaneous implantation.Described shell is connected to described trachea indirectly by fluid delivery pipe (its first end is positioned at described shell, and the second end is disposed adjacent with described trachea).Described fluid delivery pipe is connected to described trachea by " T "-shape trachea bracket, and sends interface from described trachea to the pipeline of described shell supply air as described oxygen by being formed.Described shell comprises the upper surface that can press down, and it contacts with the subcutaneous tissue of described object.When described object promotes when pressing the skin on surface a part of, can press and describedly can press surface.By pushing away the described surface that can press down, air is forced out described shell, by described fluid delivery pipe, then enters the trachea of described object.The described surface pressed down is flexible, and returns to its previous status after described object pushes away described surface.Therefore, in described shell, produce decompression, thus air is sucked described shell by described fluid delivery pipe from described trachea.

For some application, at least one layer function sexual cell layer and the Oxygen Generator comprising at least one photosynthetic oxygen supply are positioned at described shell.Typically, described functional cell is arranged in liquid or gel (such as alginate, agarose or Polyethylene Glycol (PEG)) layer, and/or is scattered in three-dimensional biodegradable or not biodegradable fibrous matrix.Described Oxygen Generator is typically connected to the support being positioned at described shell.

Described shell comprises air gap, such as, comprise the gas zone of oxygen and carbon dioxide, and it is positioned partially at the interlayer of described system.In some applications, described equipment comprises one or more photosynthetic oxygen supply, such as 2-4 oxygen supply, typically two oxygen supplies.

Typically, each photosynthetic oxygen supply comprises at least one light source and at least one deck, and such as a pair, photosynthesis source (such as algae) layer.Typically, for the application wherein using a pair algae layer, described light source is between first and second layers of described a pair algae layer.

Described multiple photosynthetic oxygen supply is arranged as layer relative to described support.Typically, the algae layer in each oxygen supply provides large surface area, and described in the surface area ratio of wherein said algae, the ratio of the surface area of functional cell is greater than 1: 1.Between each layer of photosynthetic oxygen supply, provide air gap, and its function is the pipeline as oxygen diffusion, and stores the excess of oxygen of described Oxygen Generator generation as bin.The present inventor supposes, air gap can store the oxygen molecule of the oxygen storage capacity being at least four times in liquid chamber.

Described air gap typically improves oxygen is diffused into described functional cell diffusivity from described oxygen supply.

Described photosynthetic oxygen supply typically comprise light source and at least one deck be positioned at the algae layer on agarose matrix.Typically, described photosynthetic oxygen supply comprises the first and second algae layers, and described light source is between the first and second algae layers.It should be noted that 12 layers of algae layer can be positioned at the either side of described light source at the most.In some applications, at least described in one deck, algae layer physically contacts described light source.Structure so improves the surface area of described algae, and more light can be made to contact described algae, and effectively impels oxygen-producing amount to increase thus.Described photosynthetic oxygen supply typically between the first and second functional cell layers, and is separated by the first and second respective ventilated membranes.Described first and second functional cell layers typically but the inessential opposite end being positioned at described shell.In the air gap of gas in described shell at least in part between described first functional cell layer and described first algae layer, and in air gap between described second functional cell layer and described second algae layer.

In some applications, multiple photosynthetic oxygen supply is positioned at described shell.Described oxygen supply is typically arranged between described first and second functional cell layers as a layer.Each oxygen supply is separated by the oxygen supply of air gap from next-door neighbour.Wherein said oxygen supply is comprised to the application of the first and second algae layers, each algae layer contacts the gas in each air gap be adjacent.

Typically, described air gap structure is used for storing oxygen that described algae layer produces and provides buffering.Typically, described algae produces oxygen with the speed of constant, and described functional cell is with variable speed oxygen consumption.For the application of wherein said functional cell (comprising islets of langerhans), when detect need insulin time, described functional cell produce insulin process in the speed oxygen consumption higher than its resting state.Therefore, in order to meet the variable needs of described functional cell, the bin provided by described air gap stores the excessive oxygen that described Oxygen Generator produces.Alternatively or additionally, described air gap can make oxygen diffuse to described functional cell from described oxygen supply.In this type of application, described shell typically comprises the passage be communicated with described air gap, and described channels configuration is used for collecting oxygen from described air gap, and is used for described oxygen guiding ventilated membrane, ventilated membrane the most at last oxygen diffuse to described functional cell.

Typically, described Oxygen Generator structure is used for described functional cell oxygen supply, and be used for the described functional cell of maintenance in the time (such as at least several weeks or several months) before described shell vascularization.Described Oxygen Generator is to during described cell oxygen supply wherein, and described cell typically secretes the factor of induction around the vascularization in the fibrotic tissue of described shell.When described fibrotic tissue vascularization, due to the blood vessel tissue's transhipment oxygen from new life, even if when the oxygen not having described Oxygen Generator to produce, the cell of described transplanting also can be survived usually.

The use of photosynthetical system such as photosynthetic algae and light source (is incorporated to herein by quoting) in the U.S. Patent Application Publication 2005/0136092 of open WO01/50983 or Rotem of the PCT of the people such as Vardi to be stated.

In some applications, described support comprises support, and described support holds the algae on agarose matrix.

In some applications, each algae layer is positioned at ventilated membrane, and is adjacent to arrange by described membrane-enclosed algae and described light source.

For some application, described film is connected to described support, and wherein air gap is between described algae layer and described light source.In this type of application, and the surface of the described algae away from light source (namely away between the surface of the algae of described light source and the surface away from the adjacent algae layer of light source) is adjacent to provide the first air gap, and and the surface of the described algae of contiguous light source (namely between light source and the surface of algae being close to described light source) be adjacent to provide interstice.Described first and second air gaps can make oxygen diffuse in described shell by two surfaces (i.e. the surface away from light source of described layer and the surface of contiguous light source) of described layer, improve the speed that oxygen spreads from described algae layer thus.Described algae (i.e. surface of described contiguous light source) near the layer nearest from described light source produces maximum oxygen.Can to be entered in described air gap by the diffusion into the surface of described contiguous light source from the oxygen near described, and need not first by described algae layer diffusion, then by the described diffusion into the surface away from light source to described air gap.

Be positioned at the application of described support for wherein at least two photosynthetic oxygen supplies, the algae layer in each oxygen supply is thinner, and its width is 150 μm-500 μm, typically, and about 200 μm.The width of described algae layer can make: (a) light is by the algae layer of described first oxygen supply, through air gap, then the algae layer of adjacent second oxygen supply is arrived, (b) oxygen is strengthened from the algae adjacent with described light source, by the diffusion of described algae layer, finally diffuse to described air gap.The width of described algae layer shortens oxygen by the time needed for described algae layer transhipment, impels oxygen by described layer thus and strengthens to described air gap diffusion.This diffusion strengthened can make described device supply enough oxygen more quickly to meet the keto consumpting speed of described functional cell.In addition, oxygen spreads the risk contributing to reducing the algae oxygen intoxication be disposed adjacent with described light source from the algae be disposed adjacent with described light source.

For the application that wherein said functional cell is islets of langerhans, described oxygen supply is typically with about 4-40 micromole/hours every 100,000 speed of islets of langerhans of transplanting to described islets of langerhans oxygen supply, or suitably according to type and the quantity of functional cell, and/or the body weight of described object.

Therefore, according to application more of the present invention, provide equipment, it comprises:

Shell, it is configured to implant in subject's body;

Functional cell, it is connected with described shell;

Oxygen source, its structure is used for described functional cell oxygen supply; With

The oxygen be connected with described shell sends interface, and its structure is used for receiving oxygen from described oxygen source, and is used for promoting to described functional cell transhipment oxygen, and described shell is positioned at the body of described object.

For some application, described functional cell comprises the cell being arranged in islets of langerhans.

For some application, described oxygen source comprises multiple gases.

For some application, described oxygen source comprises the oxygen carrier of preoxygenation.

For some application, described oxygen is sent interface and is reversibly connected with described oxygen source.

For some application, constructing described shell is enough at the 12 little oxygen-containing gas amounts maintaining described functional cell within the time of 2 weeks to provide.

For some application, shape described shell with provide stretch into described object tissue in multiple thrusts, described thrust structure is used for absorbing oxygen from the vascular system of described object.

For some application, described functional cell is arranged at least one hydrogel layer, and described hydrogel layer structure is used for the health of the immunity described cell of isolation and described object.

For some application, described shell of shaping is to provide oxygen bin layer, and described functional cell is arranged at least the first and second hydrogel layers, described first and second layers of either side being positioned at described oxygen bin layer.

For some application, the size of described oxygen bin layer is the longest, longer than size the longest in described first and second functional cell layers, and described oxygen bin layer is provided for the surf zone absorbing oxygen from the peripheral vascular system of described object.

For some application, described oxygen bin layer of shaping is to provide series of passages, and described passage is convenient to the orientation transhipment of fluid in described oxygen bin layer.

For some application, described oxygen bin layer comprises at least one valve, and described valve constitution is used for being convenient to the orientation transhipment of fluid in described oxygen bin layer.

For some application, construct described shell with near the thoracic cavity of implanting described object, and construct described shell with the motion in the thoracic cavity along with described object, described shell response motion, thus oxygen is circulated in described bin layer.

For some application, described oxygen bin layer comprises hydrogel, and described hydrogel is finalized to define the passage that structure is used for being convenient to the orientation transhipment of oxygen in described bin layer.

For some application, described oxygen bin layer comprises described oxygen and sends interface, and described oxygen is sent interface and can be connected with described oxygen source, and receives oxygen from described oxygen source.

For some application, described oxygen is sent interface and is comprised interface between one of described bin layer and described first and second cellular layers.

For some application, described oxygen bin layer air inclusion.

For some application, described oxygen bin layer comprises oxygen carrier.

For some application:

In first time period, described Interface Construction is used for being convenient to:

Described oxygen source is connected with described shell,

From described oxygen source to the cell oxygen supply be connected with described shell, and

The connection at described oxygen source and described interface is disconnected after oxygen supply, and

In the second time period, described Interface Construction is used for being convenient to:

Described oxygen source is connected with described shell,

The connection at described oxygen source and described interface is disconnected after oxygen supply.

For some application:

Described interface comprises transparent surface,

Described equipment also comprises pin, and described pin is configured to utilize described pin transdermal to pierce through described surface,

Described shell can be connected with described oxygen source indirectly by described pin, and

Described pin is convenient to from described oxygen source to described cell oxygen supply.

For some application, described shell of shaping is to define upper surface, and described transparent surface comprises the upper surface of described shell.

For some application, described equipment comprises at least one oxygen and sends opening, described oxygen is sent opening and is had upper surface and pipe, described Guan Qi first end is connected with described opening and is connected with described shell at its second end, and the upper surface of wherein said opening comprises transparent surface that can be penetrated by described pin.

For some application, described opening is connected with the upper surface of described shell.

For some application, described opening is arranged away from described shell.

For some application:

Described interface comprises at least one that be communicated with described casing fluid and enters fluid hose,

Enter fluid hose described in described shell can pass through indirectly to be connected with described oxygen source, and

Described pipe is convenient to from described oxygen source to described cell oxygen supply.

For some application, described in structure, enter the body that fluid hose is transdermally positioned at described object.

For some application, described shell of shaping to define oxygen bin, to store the oxygen being supplied to described shell from described oxygen source.

For some application, described oxygen bin structure is used for the storing fluids at pressures at least 1atm.

For some application, the volume of described bin is 100ml-300ml.

For some application, described oxygen bin air inclusion.

For some application, described oxygen bin comprises structure and is used for the oxygen carrier of the excess of oxygen absorbed in described oxygen bin.

For some application, described equipment comprises the ventilated membrane between described bin and described functional cell.

For some application:

Described oxygen is sent interface and is comprised at least one that be communicated with described casing fluid and enter fluid hose, and

The first end of described pipe is reversibly connected with described oxygen source, enables described oxygen source thus by described pipe to described functional cell oxygen supply.

For some application, enter fluid hose described in structure and be transdermally positioned at described subject.

For some application, described equipment comprise be communicated with described casing fluid go out fluid hose, and go out fluid hose described in structure and be used for promoting that fluid is transported to the outside of described shell in described shell.

For some application, described in structure, go out the body that fluid hose is transdermally positioned at described object.

For some application, described in go out fluid hose structure and be used for being convenient to described fluid from passive transport in described shell, and enter fluid hose described in passing through to described shell oxygen supply.

For some application, described equipment also comprises suction source, and described suction source structure is used for being convenient to active withdrawn fluid in described shell.

For some application, described oxygen is sent interface and is comprised transparent surface.

For some application, described equipment comprises the pin with at least one room, and described pin can be connected with described oxygen source, and is configured to transparent surface that transdermal pierces through described shell.

For some application, at least one room described structure is used for being convenient to send oxygen from described oxygen source to the described functional cell be connected with described shell.

For some application:

At least one room described comprises the first Room and the second Room,

Described first Room structure is used for being convenient to send oxygen from described oxygen source to the described functional cell be connected with described shell, and

Described second Room structure is used for being convenient to the external transhipment fluid to described object in described shell.

For some application, described second Room structure is used for being convenient to described fluid from passive transport in described shell, and by described first Room to described shell oxygen supply.

According to application more of the present invention, also provide the method using and comprise the equipment of implantable shell, described implantable shell comprises functional cell and oxygen sends interface, and described method comprises:

In first time period:

Described oxygen source is connected with described interface;

From described oxygen source to described cell oxygen supply; With

Disconnect the connection at described oxygen source and described interface; And

In the second time period:

Described oxygen source is connected with described interface; From described oxygen source to described cell oxygen supply; With

Disconnect the connection at described oxygen source and described interface.

For some application, described functional cell comprises the cell being arranged in islets of langerhans, and comprises from described oxygen source to described islets of langerhans oxygen supply from described oxygen source to described cell oxygen supply.

For some application, described method comprises promotion fluid from described shell passive transport and to described shell oxygen supply during described first and second time periods.

For some application, described method comprises from described shell initiatively withdrawn fluid and to described shell oxygen supply during described first and second time periods.

For some application, described method comprises the speed regulated from described bin to described functional cell transhipment oxygen.

For some application, regulate the speed of transhipment oxygen to be included in described bin and provide oxygen carrier, described oxygen carrier absorbs oxygen excessive in described bin and in low-oxygen environment, discharges described oxygen.

According to application more of the present invention, also provide equipment, it comprises:

Shell, it is configured to implant in subject, described shell:

Be finalized to define oxygen bin, and

Comprise the upper surface that it is pliable and tough;

Functional cell, it is connected with described shell; And

The pipe be connected with described shell, the first end of described pipe is communicated with described bin fluid, and its second end is configured to the gas fluid communication with described object, described pipe structure be used for being convenient to respond the upper surface imposing on described shell thrust and to described functional cell transhipment oxygen.

For some application, construct described shell away from described trachea.

For some application, construct described upper surface so that pumped into described shell from described trachea by gas.

For some application, construct thrust that described upper surface applies with Ying Xiangqi and correspondingly air extruded described bin and shifted to described trachea by described pipe.

For some application, after described upper surface applied thrust, construct described upper surface to reduce the pressure in described bin, and pass through described pipe from described trachea by bin described in air intake.

For some application, described method also comprises provides oxygen bin layer, and described functional cell is arranged in the first and second hydrogel layers, described first and second layers of either side being positioned at described oxygen bin layer.

For some application, described bin layer structure is used for absorbing oxygen from the peripheral vascular system of described object.

For some application, described oxygen bin layer is communicated with the first end of described pipe, and receives oxygen by described pipe from described trachea.

According to application more of the present invention, go back supplying method, it comprises:

To implant under incrustation in subject, described shell of shaping is to define oxygen bin and to provide the pliable and tough upper surface contacted with the subcutaneous tissue of described object;

Implanted by the Part I of pipe in the trachea of described object, the second end of described pipe is communicated with the oxygen bin of described shell; With

By promoting that to the upper surface applied thrust of described shell oxygen transports oxygen bin into described shell and to described cell traffic from described trachea.

For some application, applied thrust comprises to be forced air to discharge described bin and enters in the trachea of described object.

Shell, it is configured in insertion objects body;

One or more photosynthetic oxygen supply, it is positioned at described shell;

At least one layer function sexual cell layer, it is positioned at described shell, and structure is used for receiving oxygen from described one or more oxygen supply; With

Gas, it can make oxygen by it from described one or more oxygen supply to described cell traffic, and described gas is at least in part at described functional cell layer and described at least one between oxygen supply.

For some application, described functional cell comprises islet cells.

For some application, described gas comprises oxygen and carbon dioxide.

For some application, described shell comprises the semipermeable membrane with molecular cut off, and described film is arranged relative to described functional cell with the body fluid of molecular weight higher than described molecular cut off preventing described functional cell from contacting described object.

For some application, described film comprises ventilated membrane.

For some application, each photosynthetic oxygen supply comprises:

Light source; With

At least one deck first algae layer, it arranges and is used for receiving the light from described light source.

For some application, described equipment comprises the film between described oxygen supply and described functional cell, constructs the molecular cut off of described film to limit algae by described film.

For some application, the input power of described light source is 5mW/ (cm ²algae) to 50mW/ (cm ²algae).

For some application, the illumination energy being imposed on described algae by described light source is 0.2mW/ (cm ²algae) to 2.0mW/ (cm ²algae).

For some application, the width of described first algae layer is 100 μm to 2000 μm.

For some application, the width of described first algae layer is 100 μm to 300 μm.

For some application, described at least one deck algae layer contacts with described gas.

For some application, described gas fraction ground is between described algae layer and described light source.

For some application, described at least one deck algae layer comprises the first and second algae layers, and described light source is between first and second layer described.

For some application, described first and second algae layers all contact with described gas.

For some application, one or more layers functional cell layer described comprises the first and second functional cell layers, and described first and second functional cell layers are communicated with described first and second algae layers.

For some application, the spacing of described first functional cell layer and described first algae layer is 1000 μm to 6000 μm.

For some application, the spacing of described first functional cell layer and described first algae layer is 100 μm to 500 μm.

For some application, described gas at least in part between described first algae layer and described first functional cell layer, and between described second algae layer and described second functional cell layer.

For some application, the spacing of described first functional cell layer and described first algae layer is 1 μm to 1000 μm.

For some application, described light source comprises the first light source, described first configurations of light sources is at least first surface optical communication with described first algae layer, and described equipment also comprises secondary light source, described secondary light source is configured at least first surface optical communication with described first algae layer, and described first algae layer is between first and second light source described.

For some application:

Described equipment comprises the second algae layer, described second algae layer and described secondary light source optical communication,

Described gas at least in part between described first and second algae layers, and

The first surface of light by described second algae layer and to described first algae layer from described secondary light source is propagated.

For some application:

Described one or more photosynthetic oxygen supply comprises the first and second oxygen supplies,

Described first oxygen supply comprises described first algae layer and described first light source,

Described second oxygen supply comprises described second algae layer and described secondary light source,

Light from described first light source is set to provide light for described first algae layer and at least part of described second algae layer, and

Light from described secondary light source is set to provide light for described second algae layer and at least part of described first algae layer.

For some application, the width of described second algae layer is 100 μm-2000 μm.

For some application, the width of described second algae layer is 100 μm-300 μm.

For some application, described one or more photosynthetic oxygen supply comprises multiple oxygen supply.

For some application, described multiple oxygen supply separates with one of adjacent oxygen supply the region that width is 100 μm to 300 μm separately.

For some application, described equipment comprises the passage with described regional connectivity, and described channels configuration is used for from the oxygen of described region collection part and to described functional cell transhipment oxygen.

For some application, described gas is at least in part between each photosynthetic oxygen supply.

For some application, each photosynthetic oxygen supply comprises:

Light source; With

At least one deck algae layer, it arranges and is used for receiving the light from described light source.

For some application, described at least one deck algae layer comprises the first and second algae layers, and described light source is between described first and second algae layers.

Shell, it has at least one outlet;

One or more photosynthetic oxygen supply, its be positioned at described shell and with described outlet; With

Gas, its oxygen that described one or more oxygen supply can be made to produce is transported to described outlet by it, and described gas is at least in part in described outlet and described at least one between oxygen supply.

For some application, each photosynthetic oxygen supply comprises:

Light source; With

For some application, the illumination energy imposing on described algae layer is 0.2mW/ (cm ²algae) to 2.0mW/ (cm ²algae).

For some application, the width of described first algae layer is 100 μm-2000 μm.

For some application, the width of described first algae layer is 100 μm-300 μm.

For some application:

For some application, described first and second algae layers all with described light source contacts.

For some application, construct described shell with in insertion objects body, and construct described gas and transported to described outlet from described photosynthetic oxygen supply by it to make oxygen, be transported to thereafter near in the subject's body outside described shell.

For some application, described shell comprises the semipermeable membrane with molecular cut off, and described film is arranged relative to described shell with the body fluid of molecular weight higher than described molecular cut off preventing described photosynthetic oxygen supply from contacting described object.

For some application, described film comprises ventilated membrane.

Shell;

At least the first photosynthesis active layer, it is positioned at described shell, and described layer has at least first surface;

The first surface optical communication of at least the first light source and described first photosynthesis active layer;

At least first surface optical communication of secondary light source and described first photosynthesis active layer; With

Gas, it can make oxygen be transported from described first photosynthesis active layer by it.

For some application, the first surface in described photosynthesis source contacts with described gas.

For some application, described photosynthesis source and described first light source contacts.

For some application, the input power of described first and second light sources is respectively 5mW/ (cm ²algae) to 50mW/ (cm ²algae).

For some application, the illumination energy that described first and second light sources impose on described algae is 0.2mW/ (cm ²algae) to 2.0mW/ (cm ²algae).

For some application, the width of described photosynthesis active layer is 100 μm-2000 μm.

For some application, the width of described photosynthesis active layer is 100 μm-300 μm.

For some application:

Described at least the first photosynthesis active layer comprises the first and second photosynthesis active layer, described second photosynthesis active layer and described secondary light source optical communication,

Described gas at least in part between described first and second photosynthesis active layer, and

The first surface of light by the described second layer and to described ground floor from described secondary light source is propagated.

For some application, the width of the described second layer is 100 μm-2000 μm.

For some application, the width of the described second layer is 100 μm-300 μm.

For some application, described shell comprises at least one layer function sexual cell layer, its structure is used for receiving oxygen from described photosynthesis source, and described gas is at least in part between described cellular layer and described photosynthesis active layer, and construct described gas with make oxygen from described photosynthesis source by it to described cell traffic.

For some application, described functional cell comprises islet cells.

For some application, described photosynthesis source comprises algae, and described equipment also comprises the film between described photosynthesis source and described functional cell, and the molecular cut off constructing described film is shifted by described film to limit algae.

For some application, described film comprises ventilated membrane.

For some application, construct described shell with in insertion objects body, and construct described gas with make oxygen from described photosynthesis source by its to the described subject's body outside described shell near transhipment.

For some application, described shell comprises the semipermeable membrane with molecular cut off, and described film is arranged relative to shell with the body fluid of molecular weight higher than described molecular cut off preventing described photosynthesis source from contacting described object.

For some application, described film comprises ventilated membrane.

The present invention is understood more fully by the application of following detailed description and accompanying drawing, wherein:

Accompanying drawing is sketched

Figure 1A-B is the schematic diagram of shell, and according to application more of the present invention, described shell comprises transparent surface and case function sexual cell;

Fig. 2 is the schematic diagram that application more according to the present invention are connected to the shell of multiple liquid delivery opening;

Fig. 3 is the schematic diagram that other application more according to the present invention are connected to the shell of multiple liquid delivery opening;

Fig. 4 A-B be application more according to the present invention by two-layer functional cell around the schematic diagram of oxygen bin layer;

Fig. 5 A-C is the schematic diagram that application more according to the present invention are connected to the shell of the trachea of object indirectly;

Fig. 6 and 7 is that application more according to the present invention are connected to into fluid hose and the schematic diagram of shell going out fluid hose and case function sexual cell;

Fig. 8 is the schematic diagram according to application Oxygen Generators more of the present invention;

Fig. 9 is the schematic diagram of shell, and according to application more of the present invention, described shell comprises Oxygen Generator and the functional cell layer of Fig. 1;

Figure 10-12 is that the chart of parameter of the simulation of calculating according to application Oxygen Generators more of the present invention represents;

Figure 13 is according to application more of the present invention, the schematic diagram that oxygen flows between Oxygen Generator and functional cell; With

Figure 14 is according to other application more of the present invention, comprises the schematic diagram of the shell of shown Oxygen Generator.

Accompanying drawing describes in detail

With reference to figure 1A-B, it is the schematic diagram of system 20, and according to application more of the present invention, described system 20 comprises the implantable subcutaneous shell 24 containing functional cell layer 32 (being such as placed in the islets of langerhans of transplanting).Shell 24 comprises support 25 (such as organosilicon or metal), and functional cell layer 32 and the surface 28 comprising transparent material (such as rubber, organosilicon or plastics) separate by it.Typically, upper surface 31, namely the surface contacted with the subcutaneous tissue of object 22 of shell 24, comprises transparent surperficial 28.Surface 28 is used as oxygen and sends interface 27, and it is pierced through by disposable pin 50 is convenient to close to shell 24.Comprise the oxygen source (not shown) in oxygen-bearing fluid source, such as, container, as syringe, is connected with pin 50, and by pin 50, oxygen-bearing fluid is supplied to the functional cell (such as islets of langerhans) be placed in shell 24.In some applications, described oxygen source comprises air.Or described oxygen source comprises pure oxygen.

Typically, layer 32 comprises 40,000-400,000 islets of langerhans, and such as, typically, 400,000 islets of langerhans, they are distributed in monolayer 32 equably.Be suitable for specific application, islets of langerhans number also can exceed this scope.In some applications, in the following manner (structure shown in Fig. 2) arranges islets of langerhans: the islets of langerhans that the islets of langerhans every string in its middle level 32 is adjacent row staggers (offset).The volume being 8-40 μm or 40-200 μm to make partial pressure of oxygen in each islets of langerhans and concentration are to the islets of langerhans oxygen supply in layer 32.

In some applications, described oxygen source comprises multiple gases (comprising oxygen).Described gas is placed in container, and its pressure is 1atm or higher.Typically, in order to maintain the balance of gas concentration lwevel between shown enclosure and outside, described oxygen source comprises the carbon dioxide of about 5%.For some application, described oxygen source comprises fluid, described fluid comprises oxygen carrier (such as based on the oxygen carrier of hemoglobin, as the hemoglobin of chemical modification, or " microvesicle " (it comprises fluorocarbon such as R-4112 or perfluorodecalin)), described oxygen carrier before being injected in shell 24 by oxygenation.The compressed oxygen that this carrier is convenient to larger volume is transported in shell 24.

Typically, described functional cell layer 32 is in liquid or gel (such as alginate, agarose or Polyethylene Glycol (PEG)) layer, and/or is scattered in three-dimensional biodegradable or not biodegradable fibrous matrix.In some applications, layer 32 comprises and holds described functional cell and be used for the alginate sheet of immune isolated cell.This application can be implemented with the technical combinations described in the U.S. Provisional Patent Application 61/192,412 (it is incorporated to herein by quoting) of the people such as Barkai.

Layer 32 has the interface 30 with the Body contact of object 22.Typically, other by-products of insulin and/or functional cell are released into described health by interface 30.In some applications, interface 30 comprises the surface of alginate sheet.In some applications, interface 30 comprises permselectivity membrane, its immunity is isolated the cell of described transplanting and promotes (a) molecule such as insulin from cell traffic to the health of object 22, and (b) molecule such as glucose is transported to the cell in shell 24 from the health of object 22.

Support 25 defines the space comprising oxygen bin 42, and typically its volume is 100ml-300ml, such as 150ml-200ml.Oxygen bin 42 comprises foam, such as, and open-cell silicone foam, or the air gap being used as gas container simply in this device.Bin 42 is used as the pipeline that oxygen diffuses to functional cell, and be also used as bin, described bin is supplied to the excessive oxygen of described shell by oxygen source for storing.Technology about bin 42 as herein described can be implemented with the technical combinations about air gap described in the PCT patent application PCT/IL08/001204 of the people such as Stern (being incorporated to herein by quoting).

In some applications, described shell comprises described oxygen carrier.In this type of application, described oxygen carrier is used for storing when oxygen excess or transporting oxygen and discharging oxygen whenever necessary.

The nonrestrictive mode with example, is expressed as dish type by shell 24.Such as, shell 24 can be any other applicable shape that rectangle or be suitable for is transplanted under the skin 26 of object 22.In some applications, shell 24 is shaped provide radially outstanding and towards many thrusts of (comprising vascular system) near the health of object 22 from shell 24.In this type of application, described thrust is used as oxygen and sends interface 27, is convenient to oxygen from peripheral vascular system transhipment to shell 24 by the surface area increasing shell 24.For some application, the thrust of shell 24 contains oxygen carrier, and it stores the excessive oxygen be absorbed into by described thrust in shell 24.

A period of time after in body shell 24 being implanted object 22, appropriate oxygen containing fluid is injected shell 24.(described shell also can be filled oxygen containing fluid in advance).Typically, described object 22 uses pin 50 transdermal to pierce through the surface 28 of shell 24, and the far-end of pin 50 is forward by bin 42 and close to functional cell layer 32.The distal contact of cellular layer 32 and pin 50 is prevented by the separate layer 34 of the rigidity being substantially in also defencive function sexual cell layer 32 on functional cell layer 32.Many upright supports 36 are between separate layer 34 and the surface 28 of shell 24.

For some application, shaped by separate layer 34 to define many passages 38 and 40, they promote that (a) oxygen is from bin 42 to cellular layer 32, and (b) carbon dioxide is from cellular layer 32 to the two-way transhipment of bin 42.Alternatively, oxygen is transferred to layer 32 by other approach from bin 42.

In some applications, shell 24 comprises ventilated membrane 35, such as Millipore film and/or comprise organosilyl film, and it is between functional cell layer 32 and separate layer 34.Ventilated membrane 35 is convenient to gas and is transported to functional cell layer 32 or transport from functional cell layer 32.Typically, the width of film 35 and the aperture adjustment gas speed of transporting to layer 32 and transporting from layer 32.

The enlarged image of Figure 1B represents the cross sectional view of pin 50.Pin 50 comprises two chamber pin (comprise into fluid chamber 54 and go out fluid chamber 56).The near-end of pin 50 is connected with luer adapter 52, and luer adapter 52 is convenient to connect the container (such as syringe) comprising oxygen containing fluid.Luer adapter 52 is communicated with the proximal fluid entering fluid chamber 54.In order to enter the bin 42 of shell 24, described fluid is discharged from syringe on one's own initiative by room 54, and leaves room 54 by one or more holes 55 of the far-end of pin 50.

When the fluid of elevated oxygen level injects bin 42 (i.e. direction shown in arrow 1) on one's own initiative, the fluid being in the low oxygen content in bin 42 passes through the one or more holes 57 in fluid chamber 56 and leaves bin 42 passively.The fluid of this low oxygen content by moving with the direction shown in arrow 2, and leaves pin 50 by one or more holes 59 of room 56 proximal part outside the surface of the skin 26 that is positioned at object 22.

It should be noted that exemplarily unrestricted, pin 50 comprise be respectively 55,57 and 59 3 holes, and pin 50 of can shaping is to comprise the hole 55,57 and 59 of any applicable quantity.

It should be noted that exemplarily unrestricted, multiple holes 55 of room 54 are on the substantially the same cross section of pin 50 relative to multiple holes 57 of room 56.Such as, hole 55 can be positioned on the nearer position of body part of pin 50, and hole 57 is positioned at the position compared with far-end of the body part of pin 50.

Typically, fluid injecting high for excessive oxygen content is entered bin 42.In some applications, excessive oxygen is the form of free gas.Alternatively, as described above, excess of oxygen load is on oxygen carrier.In order to ensure pass through fluid chamber 56 passive transport (it occurs together with injection) at fluid after, keep enough oxygen containing fluids in bin 42, excessive oxygen is provided.

Typically, with the size meeting shell 24 and the volume of functional cell amount be placed in one and concentration to shell 24 oxygen supply.In addition, the oxygen amount being delivered to shell 24 depends on the composition of the fluid be injected in shell 24.Namely with the fluid-phase ratio comprising free oxygen of same volume, the fluid comprising the oxygen carrier of preliminary filling of certain volume can make the functional cell in shell 24 maintain the longer time.Usually, oxygen is sent interface 27 and is promoted to be enough to content with funtion sexual cell at special time, and such as, the volume of the keto consumpting speed in 12 hours-2 weeks and concentration are repeatedly to described functional cell oxygen supply.

Exemplarily unrestricted, following table illustrates, according to various application of the present invention, just comprises the opinion with the size of the shell 24 of various 400,000 islets of langerhans be distributed in shell 24, the pre-period parameters relevant to oxygen source:

Wherein:

Cellular layer # is the cell number of plies (1 layer (as in Figure 1B) or 2 layers (as in Fig. 7));

CTC is the centre-to-centre spacing between islets of langerhans, namely from the distance at center to the center of adjacent islets of langerhans of an islets of langerhans;

ID is islets of langerhans density (islets of langerhans/cm ²);

Diam. be the diameter (mm) of each alginate sheet;

K alginate are that oxygen is at alginate sheet (mm ²/ s) alginate in infiltration coefficient;

Pmin is the minimum dividing potential drop of oxygen in bin 42, and to make partial pressure of oxygen in each islets of langerhans for 8-200 μm, this is enough to maintain functional islets.Typically, the oxygen in bin 42 can be reduced to minimum about 90 μm, then returns to about 215 μm (being equivalent to about 21% oxygen).It should be noted that described dividing potential drop can return to the value being greater than 215 μm for some application, such as, bin 42 can contain the oxygen of 21%-50% or 50%-100%; And

W is the thickness/width of bin 42.

Typically, shell 24 comprises the functional cell monolayer 32 of the single alginate thin slice being arranged in Thief zone coefficient.Typically, functional cell layer 32 comprises 300,000-500, and 000 islets of langerhans (such as about 400,000), density is 3200-5000 islets of langerhans/cm ², such as, 3700-4000 islets of langerhans/cm ².

Usually, the diameter of shell 24 is 100mm-150mm, such as 125mm, and its width is 20mm-100mm, such as 25mm.Typically, by the air Injection shell 24 containing 21% oxygen.Typically, with 30-500 μM, the concentration of such as 57-215 μM is to shell 24 oxygen supply.Structure shell 24 is with the gas containing 1atm or more high pressure.

According to the interval (such as at least one times/week, typically, a times/day) of regulation, pin 50 is sent interface 27 by oxygen and is inserted in shell 24 again by object 22.According to interval so, oxygen source (such as syringe or pre-filled pillar) is connected to pin 50, and supplies oxygen containing fluid to the islets of langerhans in shell 24.

It should be noted that exemplarily unrestricted, pin 50 is expressed as and comprises two chamber pin.Such as, pin 50 can comprise single chamber formula pin.In this type of application, described oxygen source can be connected to pump, described pump promotes that the fluid of the elevated oxygen level of (1) part is injected into shell 24 gradually on one's own initiative from described oxygen source, and the fluid of (2) low oxygen content initiatively (or passive) discharges the circulation between shell 24 gradually.For some application, user can implement the operation substituting described pump with identical operation described herein.

It should be noted that transparent surperficial 28 of shell 24 only a part of upper surfaces that can define shell 24.In this type of application, the upper surface of shell 24 comprises containing transparent open region of surperficial 28.

Fig. 2 represents system 160, and according to application more of the present invention, it comprises the implantable subcutaneous shell 24 being connected to multiple fluid-infusing port 172.Upper surface 31 comprises not transparent surperficial 161 of the rigidity supported by many mechanical supports 36.Opening 172 is on upper surface 31, and comprises not transparent substrate 168 of rigidity and define the wall of open chamber 169.The upper surface of each opening comprises transparent surperficial 28, and it is used as oxygen and sends interface 27.Each pipe 170 promotes that oxygen is transferred to bin 42 from opening 172 and shifts to islets of langerhans layer 32.Each pipe 170 provides: (a) is connected to opening 172 and the first end be communicated with room 169 fluid, (b) through the main part of the side of upper surface 31 or shell 24, with the second end that (c) is communicated with bin 42 fluid of shell 24.

Protection grid 162 is positioned at the comparatively lower part of shell 24.Grid 162 for support 36 provide basis.For some application, ventilated membrane 35 between grid 162 and islets of langerhans layer 32, and is convenient to gas and is transported between bin 42 and layer 32.Second grid 164 is positioned at below islets of langerhans layer 32 and also provides support for it.Permselectivity membrane 166 is typically positioned at the interface 30 of the tissue of shell 24 and object 22.Permselectivity membrane 166 comprises the Millipore film that aperture typically is about 0.5 μm, the cell that immunity isolation is transplanted, and promote (a) molecule such as insulin from cell to the transhipment of the health of object 22, and (b) molecule such as glucose is from the health of object 22 to the cell traffic shell 24.

Typically, shell 24 is implanted after in object 22 body, with appropriate oxygen containing fluid pretreatment shell 24.(described shell also can fill oxygen containing fluid in advance).Typically, the his or her hands 21 of object 22 gropes at least one opening 172.When determining the position of opening, object 22 first pin transdermal thrusts skin 26, pierces through transparent surperficial 28 of the first opening 172 subsequently.In this type of application, described pin comprises single chamber formula pin.Typically, then object 22 gropes the second opening 172, and pierces through the surface 28 of the second opening 172 with the second single chamber formula pin transdermal.Not transparent substrate 168 of each opening 172 prevents described pin from entering shell 24 with not transparent surperficial 161 of shell 24 jointly.Described first pin is used for by reducing pressure in the room 169 of described first opening 172 from shell 24 withdrawn fluid.Because pressure reduces, fluid passes through pipe 170 from the room 169 of bin 42 suction first opening 172, finally by described first pin.The while of with withdrawn fluid, as described above, described second pin is connected to oxygen source, and promotes that oxygen containing fluid enters in shell 24.

In some applications, oxygen containing fluid is driven through described first pin, and the hypoxia fluid that shell Central Plains pre-exists thus is drawn out of shell 24 and is replaced by described oxygen containing fluid.

For some application, described first and second pins are supported by sharing structure before they pierce through the surface 28 of skin and each opening He in penetration process.

In some applications, the upper surface 31 of shell 24 is pliable and tough and transparent.This type of application in, only each substrate 168 of each opening prevent described in be needled into shell 24.

With reference to figure 3, it is the schematic diagram of the system 180 similar to the system 160 mentioned above shown in Fig. 2, according to application more of the present invention, is arranged at away from shell 24 part unlike opening 172.Outlet 172 is placed in and promotes that liquid delivery not to change the position of shell 24 substantially to shell 24 away from shell 24.

With reference to figure 4A-B, it is the schematic diagram of system 150, and according to application more of the present invention, it comprises two functional cell layers 32 around oxygen bin layer 152.Functional cell layer 32 comprises in the above described manner relative to layer 32 typically equally distributed islets of langerhans.Bin layer 152 receives and stores oxygen containing fluid (such as comprise the gas of oxygen molecule, or comprise the liquid of oxygen carrier of preliminary filling aerobic).In some applications, layer 152 comprises hydrogel, such as alginate.In some applications, layer 152 comprises gas container.

In some applications, bin layer 152 by pin (for example, referring to the mode that Figure 1A-B and 2-3 is mentioned above), or passes through into fluid hose (such as, with reference to Fig. 5 A-C and 6-7 mode hereinafter described), receive oxygen containing fluid from oxygen source.It should be noted that system 150 can independently, or can be used for bin layer 152 oxygen supply with the application combination described in Figure 1A-B, 2-3,5A-C and 6-7.Such as, bin layer 152 can comprise oxygen carrier and absorb oxygen from the vascular system of surrounding layer 152.

In some applications, bin layer 152 preload oxygen carrier (such as based on the oxygen carrier of hemoglobin, such as, the hemoglobin of chemical modification, or " microvesicle " that comprise fluorocarbon such as R-4112 or perfluorodecalin).Typically, described oxygen carrier is filled with oxygen, and is supplied to bin layer 152 with the interval of regulation after implant system 150.

Each layer 32 of cell has the interface 30 of (a) and the tissue of object 22, and (b) and as the interface of bin layer 152 of sending oxygen interface 27.In this type of application, system 150 is used as shell 24 or 124.Therefore, each layer 32 sends interface 27 with the oxygen that the interface 30 of the tissue of object 22 is used as to absorb from the vascular system around system 150 oxygen.In this type of application, arbitrary surface of each layer 32 is exposed to oxygen.That is, the surface of each layer 32 receives oxygen at interface 30 from the vascular system of object 22, and the surface of each layer receives oxygen at layer 32 and the interface of bin layer 152 from bin layer 152.

Although it should be noted that and two cellular layers 32 are only shown, the cellular layer of any applicable quantity can be connected to bin layer 152.It shall yet further be noted that exemplarily unrestricted, layer 32 is expressed as flat.Such as, can setting layer 32 to limit along the various thickness of plate.In some applications, Ceng32 center is thicker and thinner along its edge.

In some applications, system 150 is integrated into (Figure 1A-B and 2-3 is mentioned above in reference, and reference Fig. 5 A-C as mentioned below) in shell 24, or is integrated in reference Fig. 6-7 shell 124 hereinafter described.Application in shell 24 or 124 is integrated into for wherein system 150, the interface 30 of ground floor 32 and the contact tissue of object 22, and the interface 30 of the second layer 32 contacts with the bin 42 of shell 24.In this type of application, be used as oxygen with the interface 30 of the contact tissue of object 22 and send interface 27, because interface 30 promotes that oxygen is transported to the islets of langerhans layer 32 from the peripheral vascular system of object 22.

Typically, the diameter of layer 152 is about 10cm, and its thickness is 1mm-3cm, such as about 2mm, and the less 8cm that is about of the diameter of each islets of langerhans layer 32, and its thickness is less than 1mm.Bin layer 152 causes more greatly the layer 152 of part to be exposed to the tissue of object 22 than the diameter of islets of langerhans layer 32.These parts produce larger surface area, make bin layer absorb oxygen from the peripheral vascular system of object 22.The application of oxygen carrier is comprised, the excess of oxygen in described oxygen carrier absorbed layer 152 for wherein bin layer.

Fig. 4 B represents the cross section of oxygen bin layer 152.Layer 152 comprises wall 153, and wall 153 comprises flexible material such as organosilicon.Wall 153 defines series of passages 157, for transporting oxygen by layer 152 orientation.Typically, layer 152 comprises check valve, such as mechanical valve or motor valve, and it promotes the orientation transhipment of oxygen containing fluid in passage 157.Typically, in response layer 152, oxygen increases and increases pressure in layer 152, thus causes this fluid delivery passively.For some application, the thoracic cavity of the implanted object 22 of system 150.In this type of application, layer 152 answers the motion in thoracic cavity in respiratory and corresponding sports to cause the circulation of the fluid in layer 152.

It should be noted that exemplarily unrestricted, quantity and the space structure of wall 153 and valve 155 are shown, and layer 152 can comprise valve and the wall of any applicable quantity, they by oxygen conductance to any applicable direction.Can be directed by wall 153, make it provide the passage 157 that shape is different from diagram.

Fig. 5 A-C represents the system 130 comprising implantable subcutaneous shell 24, according to application more of the present invention, constructs described shell and receives oxygen with the trachea 100 from object 22.Shell 24 is typically placed in away from trachea 100 part, and is connected with it by air transhipment pipe 132.Typically, shell 24 is placed in the abdominal part of object 22.For some application, shell 24 is placed in the thoracic cavity of object 22.

Transhipment pipe 132 typically comprises organosilicon, and is connected to shell 24 at its first end 134, is communicated with thus with bin 42 (as shown in Fig. 5 A-B) fluid.Second end of pipe 132 and " T "-shape trachea bracket 136 (as shown in Fig. 5 C) base portion be connected.142 of trachea bracket 136 and 144 each ends are placed in the trachea 100 of object 22.142 ends and 144 ends define the end of the vertical cavity of trachea bracket 136, and are used as diverter by air guide pipe 132, finally arrive shell 24 to make directed air.Like this, trachea bracket 136 is used as oxygen and sends interface 27.

Shell 24 comprises the support 25 supporting upper surface 31.In the application shown in Fig. 5 A-B, upper surface 31 is pliable and tough and can presses down.Subcutaneous transplantation shell 24, to make when object 22 presses the skin on surface 31 and correspondingly forces in surperficial 31, surface 31 can be pressed down by object 22.As shown in Figure 5 A, in response to this pressing, air is discharged bin 42 (as shown by arrows) by pipe 132, and is flowed in trachea 100 by trachea bracket 136.

Fig. 5 B presentation surface 31 is decontroled after being pressed.Because surface is 31 flexible, as illustrated, surface 31 returns to its original shape, and this makes pressure in shell 24 reduce, and forces and enter (as shown by arrows) the bin 42 of shell 24 containing oxygen air from trachea 100.Therefore, system 130 is used as pumping mechanism, and this can make object 22 will pump into shell 24 from trachea 100 containing oxygen air.

With reference to figure 6-7, it is the schematic diagram of system 120, and according to application more of the present invention, it comprises to enter fluid hose 60 and transdermal with transdermal and go out the implantable subcutaneous shell 124 that fluid hose 62 fluid connected sum is connected.The respective first end 64 and 66 of pipe 60 and 62 is placed in shell 124, and the skin 26 that respective the second end 61 and 63 of pipe 60 and 62 is positioned at object is outside.The end 61 entering fluid hose 60 is used as oxygen and sends interface 27.Each stopper 80 is connected to 61 and 63 of pipe 60 and 62 respectively and respectively holds, and without pipe 60 and 62 time be used for reversibly sealing described pipe 60 and 62.

It should be noted that exemplarily unrestricted, pipe 60 and 62 is positioned at the homonymy of shell 124.Such as, pipe 60 and 62 can be positioned at the opposite side of shell 124.

Shell 124 comprises support 125, as the support 25 that reference Figure 1A-B is mentioned above.Support 125 around bin 42, and supports one or more layers functional cell layer 32.Typically, a layer 32 is positioned on the upper surface of shell 124, and another layer 32 is positioned on the lower surface of shell 124.Each ventilated membrane 35 is between each functional cell layer 32 and bin 42.Hold 400 for its housing 124, in the application of 000 islets of langerhans, each functional cell layer 32 comprises 200,000 islets of langerhans.Hold 40 for its housing 124, in the application of 000 islets of langerhans, each functional cell layer 32 comprises 20,000 islets of langerhans.

Oxygen source (not shown), such as, the container comprising oxygen containing fluid source, as syringe or pre-filled post (pre-filled cartridge), is sent interface 27 at oxygen and is connected to pipe 61.Described oxygen source passes through to supply described fluid into fluid hose 61 to shell 124.In some applications, described oxygen source comprises other mixture of air or gas.Alternatively, described oxygen source comprises pure oxygen.In some applications, described oxygen source comprises the liquid containing oxygen carrier mentioned above.With to shell 124 oxygen supply simultaneously, the fluid of low oxygen content passes through fluid hose 62 and discharges in shell 124.In some applications, in shell 124, produce pressure owing to injecting the fluid of elevated oxygen level, thus described fluid is discharged from shell 124 passively.Alternatively or extraly, connect suction source at the end 63 of pipe 62, and in shell 124 withdrawn fluid on one's own initiative.

As illustrated, the first end 64 of pipe 60 is positioned at shell 124, and from the end 66 of pipe 62 distance significantly (be such as greater than shell 124 the longest measure 50%, or be greater than shell 124 the longest measure 75%).Such structure can make fluid pass through to be transported to shell 124 into fluid hose 60 from described oxygen source, makes to draw back immediately and be down to minimum by going out fluid hose 62 by the probability of the fluid transported simultaneously.

In application more of the present invention, hygroscopicity element (not shown) is arranged at vicinity in shell 124 and goes out the end 66 of fluid hose 62, or other places in described shell.Described hygroscopicity element helps lend some impetus to the wetting balance in shell 124.Shell 24 (mentioned above with reference to Figure 1A-B) also can comprise described hygroscopicity element.

In some applications, the bin 42 of shell 24 comprises foam, such as open-cell silicone foam, and the distance between being used for keeping also supports functional cell layer 32 (mode with similar to the support 36 with reference to Figure 1A-B shell 24 mentioned above).Alternatively or in addition, support 36 is integrated in shell 124.

With reference to figure 1A-B and 2-7.After supplementing shell 24 and 124 with the fluid of elevated oxygen level, send interface 27 from oxygen and pull down described oxygen source.According to the interval of regulation, such as every 1-7 days are once, or every 7-35 days once, described oxygen source is connected to interface 27 and to shell 24 and 124 oxygen supply by user.

With reference to figure 3,4,5A-C and 6-7.The bin layer 152 (mentioned above with reference to Fig. 4) of system 150 can be sent interface 27 with any oxygen mentioned above with reference to Fig. 3,5A-C and 6-7 and combinationally use.That is, in some applications, bin layer 152 is connected to pipe 170, and with reference to Fig. 3 mode mentioned above by being connected to opening 172 oxygenation of pipe 170.For some application, bin layer 152 is connected to pipe 132, and it receives oxygen-containing gas with the form mentioned above with reference to Fig. 5 A-C from trachea 100.In some applications, bin layer 152 is connected to transdermal pipe 60 and 62, and receives oxygen containing fluid in the mode mentioned above with reference to Fig. 6-7 from entering fluid hose 60.

Typically, the layer 32 and 152 of system 150 is pliable and tough, and be configured to implant object 22 thoracic cavity near.In this type of application, bin layer 152 responds the natural motion in the thoracic cavity of described object 22 and moves and distortion.Therefore, the oxygen containing fluid being positioned at bin layer 152 is forced in and wherein moves, to make described fluid in layer 152 and surrounding layer 32 to islets of langerhans circulates.In some applications, layer 152 comprises liquid or gel, such as alginate.Its middle level 152 is comprised to the application of gel, can setting layer 152 to define passage and/or valve, described passage and/or valve produce the path be used at the described oxygen containing fluid of layer 152 interior orientation transhipment.

Refer again to Figure 1A-B and 2-7.Equipment as herein described can comprise functional cell layer 32, and functional cell layer 32 comprises independently, or grid 162 and 164 mentioned above and/or film 35 and 166 combine with reference Fig. 2.

Refer again to Figure 1A-B and 2-7.Should note, scope of the present invention comprises equipment as herein described for transplanting the purposes of functional cell except islets of langerhans (such as thyroid cell, adrenal cells, hepatocyte, and in order to secrete therapeutic protein by the cell of genetic modification).

Reference diagram 1A-B and 2-7 in addition.In some applications, shell 24 and 124 is connected to implantable subcutaneous oxygen source or bin.Described implantable oxygen source is connected to shell 24 and 124 by least one pipe.For some application, transport oxygen in the mode regulated and controled at least to a certain extent from described oxygen source to shell 24 and 124.Such as, the pipe that implanted oxygen source is connected with shell 24 or 124 can be comprised check valve (such as mechanical valve or motor valve), it contributes to regulated fluid and transports speed into shell 24 or 124.Typically, described implanted oxygen source comprises the fluid of 100ml-300ml, and wherein pressure is up to 1000atm (such as 1-10atm, 10-100atm, or 100-1000atm).

With reference to figure 8 and 9, it is the schematic diagram of system 1020, and according to application more of the present invention, it comprises structure and is used for producing oxygen respectively to the ground floor of functional cell and the Oxygen Generator 1022 of the second layer 1070 and 1074 oxygen supply.Typically, the functional cell be placed in layer 1070 and 1074 comprises islet cells.The layer 1070 and 1074 of functional cell comprises metal grill (not shown), and it comprises the substrate of adherent cell, such as liquid or gel, such as alginate, agarose or Polyethylene Glycol (PEG).Alternatively, setting layer 1070 and 1074 is to provide the biodegradable or not biodegradable fibrous matrix of the three-dimensional it being dispersed with described cell.

The layer 1070 and 1074 of Oxygen Generator 1022 and functional cell is positioned at shell 1060, and it is configured to implant in subject's body.Typically, Oxygen Generator 1022 produces the oxygen maintaining described functional cell during first vascularization be enough at the fibrotic tissue formed around shell 1060.Make described cell after the transfer at once can normal activity to the oxygen supply immediately of described cell.Typically, Oxygen Generator 1022 produces oxygen in real time by photosynthetic.For some application, described Oxygen Generator after described fibrotic tissue vascularization during in continue to described cell oxygen supply.

Fig. 8 represents Oxygen Generator 1022, and it comprises oxygen supply shell 1034, and it comprises at least one photosynthetic oxygen supply 1024 then.Each photosynthetic oxygen supply 1024 comprises light source 1028 then, and such as, at least one and light propagate the LED that component such as illumination plate is connected, and at least algae layer 1026 that arranges around light source 1028 of one deck.As illustrated, algae layer 1026 and with interval applicable distance adjacent with light source 1028 is arranged.In some applications, layer 1026 contacts light source 1028 (structure is not shown).

In some applications, the input electric power of light source 1028 is 5mW/ (cm ²algae) to 50mW/ (cm ²algae).Typically, the ratio imposing on the illumination energy of described algae layer 26 is 0.2mW/ (cm ²algae) to 2.0mW/ (cm ²algae).

In application more of the present invention, Oxygen Generator 1022 comprises the photosynthetic oxygen supply 1024 of 1 to 4 layer (such as typically, 2 layers).Each air gap 1040 is arranged with algae layer 1026 fluid flow communication of each photosynthetic oxygen supply 1024, and is placed between Oxygen Generator 1022 and functional cell layer 1070 and 1074.Photosynthetic oxygen supply layer 1024 respectively comprises one or more layers algae layer 1026.Typically, algae layer 1026 provides large surface area, and the ratio of the surface area of the surface area ratio functional cell layer 1070 and 1074 of wherein said algae is greater than 1: 1.

The air gap 1040 of system 1020 provides a kind of component, is infiltrated into the region (i.e. functional cell layer 1070 and 1074) of low concentration by this component oxygen molecule by the minimum gaseous medium of resistance from the region (i.e. algae layer 1026) of high concentration.

As illustrated, each oxygen supply 1024 comprises support 1030, and it comprises light source 1028 and described algae.Support 1030 comprises the substrate around light source 1028, such as agarose or optical clear plastics.Typically, the first and second algae layers 1026 to be arranged on support 1030 and adjacent with the first and second surfaces of light source 1028 respectively.Layer 1026 improves the surface area of the algae being exposed to the light that light source 1028 is launched relative to the position like this of light source 1028, effectively improves the photosynthetic speed of described algae.

In application more of the present invention, light source 1028 comprises the multiple LED being connected to plastics illumination plate (its conducted emission is from the light of LED).。

Referring again to Fig. 8 and 9.Each photosynthetic oxygen supply 1024 separates with next oxygen supply 1024 by air gap 1040 (air inclusion, such as, by air that oxygen and carbon dioxide strengthens).Gas contained in air gap 1040 between adjacent oxygen supply 1024 makes each algae layer 1026 be communicated with described gaseous fluid, and the oxygen that described algae produces diffuses in air gap 1040.The present inventor supposes, the diffusivity (diffusivity) that the existence increase oxygen being positioned at the gas of air gap 1040 spreads by air gap 1040 and eventually to functional cell layer 1070 and 1074.A large amount of gaseous oxygens that the gas being positioned at air gap 1040 can also make described algae produce are stored in wherein.As shown in Figure 9, being shaped to define distance D3 by each air gap 1040 between each oxygen supply 1024 (when Fig. 9, being oxygen supply 1241,1242 and 1243) is 100 μm-300 μm, such as 200 μm.

Setting bracket 1030 is to provide at least one path 10 32, and the oxygen transport that described path 10 32 is configured to be produced by oxygen supply 1024 by path 10 32 is to functional cell layer 1070 and 1074.As shown in the application in figure, passage 32 is convenient to continuous print gas between each air gap 1040 and is exchanged.Because the keto consumpting speed of described functional cell can become along with local condition's (such as blood sugar level), and because the speed that the algae in layer 1026 produces oxygen can become along with local condition (such as intensity levels), so air gap 1040 is used as oxygen bin, store the oxygen of generation until diffuse to described functional cell when the described oxygen of needs.This storage have adjusted the concentration of oxygen in shell 1060.

Therefore, when providing light with constant ratio, when every other condition is all equal, described algae produces oxygen with constant speed.Then, oxygen diffuses in air gap 1040, wherein depend on the oxygen consumption needs of described functional cell, described oxygen molecule can: (1) is by air gap 1040 and to the diffusion of described functional cell and be immediately used wherein, (2) to be stored in air gap 1040 until when described functional cell needs oxygen, or (3) when air gap 1040 is by oxygen saturation, and when described functional cell does not need or do not consume the available oxygen be stored in air gap 1040, respectively by cellular layer 1070 and 1074, by film 1072 and 1076, and to the infiltration of surrounding tissues of described object.

In addition, light regulator (not shown) is typically connected to shell 1060, the concentration be used for by regulating described algae to produce oxygen in the speed adjustment shell 1060 of oxygen.Described light regulator typically regulates the intensity of the light sent from the light source 1028 of each oxygen supply 1024, or radiative pulse rate or cycle of operation.

As shown in Figure 9, each algae layer 1026 of shaping is 10 μm-2000 μm to limit width W 2, typically, 100 μm-2000 μm, such as 100 μm-300 μm.In addition, the structure that each algae layer 1026 is plane is substantially set, is of a size of about 0.05cm × 0.05cm to about 10cm × 10cm (such as 1.3cm × 1.8cm).

Fig. 9 represents Oxygen Generator 1022, and it comprises oxygen supply 1241,1242 and 1243.The width W 2:(a of each algae layer 1026 in each oxygen supply 1024) the interior propagation from the light of light source 1028 of optimization layer 26, relative oxygen concentration contained in (b) lower layer 1026, and oxygen flow suitable between (c) promoting layer 1026 and air gap 1040.The width W 2 of algae layer 1026 can make most of described algae absorb the light sent by light source 1028 of roughly about 90%.

In addition, the width W 2 of layer 1026 promotes that light is transmitted to the algae layer 1026 of the first oxygen supply 1024 from the adjacent light source 1028 of the second oxygen supply 1024.Propagate this is because the little width of the algae layer 1026 be disposed adjacent with the light source 1028 of described second oxygen supply is convenient to the algae layer 1026 of light by algae layer 1026 and to described first oxygen supply.Such as, because the width W 2 of algae layer 1026 is thinner, the surface 1261 that the enough light that the light source 1028 of oxygen supply 1241 produces can exceed the algae layer 1026 of oxygen supply 1241 is propagated, and propagates to the surface 1263 of the algae layer 1026 of oxygen supply 1242.In addition, because the width W 2 of algae layer 1026 is thinner, light can be propagated, so the surface 1263 of the algae layer 1026 of oxygen supply 1242 also receives the light produced by the light source 1028 of oxygen supply 1242 by (and exceeding) algae layer 1026.

Therefore, the combination of the light intensity in the particular surface (being namely positioned at the surface be communicated with the light source optical of adjacent oxygen supply) of specific algae layer 1026 or the irradiance intensity of following light typically: (1) launches the light from the light source be disposed adjacent, and (2) launch the light from adjacent light source.

With reference to figure 10-12, it is that the chart of the parameter of Oxygen Generator represents according to application more of the present invention.

Figure 10 is that the chart of the light intensity of the algae layer of the different in width (namely 250 μm and 500 μm) of the photosynthetic oxygen supply be respectively disposed adjacent represents.Typically, according to Beer-Lambert law, by there is full duration (namely 500 μm) and there is each algae layer of width (namely 250 μm) of half of full duration, light exponentially level ground decay (as shown).This figure represents algae layer, and wherein: (a) 0 μm limits the surface of the algae layer be disposed adjacent with described light source, and (b) 250 μm or 500 μm limit the surface from described light source each algae layer farthest.

Therefore, be the algae layer of 500 μm for width, light intensity is from 0 μm of about 8.8uE/ (s*m ²) decay at 500 μm of about 0.3uE/ (s*m ²), namely from described light source farthest algae layer surface.By contrast, be the algae layer of 250 μm for width, light intensity is from 0 μm of about 8.8uE/ (s*m ²) decay at 250 μm of about 3.1uE/ (s*m ²), namely from described light source farthest algae layer surface.With reference to Fig. 9, as described above, in order to supplement light to the adjacent layer also received from the light of the light source on its adjacent position, by the width of described algae layer 26 is down to about 250 μm, light can by the algae layer of the first oxygen supply and to the algae Es-region propagations of the second adjacent oxygen supply.Relative to the light intensity on the surface of the algae layer of 500 μm wide, the described supplementary light on the surface of the algae layer of 250 μm wide increases the light intensity on this surface.

Although on arbitrary curve, at distance light source 250 μm place, light intensity all decays, but the light intensity that the curve representing the algae layer of 250 μm wide demonstrates on the surface (being namely exposed to described air gap and the surface be communicated with described air gap fluid) of the algae layer of 250 μm wide is stronger.This is because as above about as described in Fig. 9, the width W 2 of algae layer 1026 can make algae receive the light from the light source be disposed adjacent with described algae layer at distance light source 250 μm place, and the light of light source from adjacent photosynthetic oxygen supply.

Because compared with the algae on the surface of the algae layer of 500 μm wide, more effectively provide to the algae on the surface at the layer of 250 μm wide and be enough to carry out photosynthetic light, so the light intensity on the surface of the algae layer of 250 μm wide optimizes total oxygen-producing amount of whole algae layer.

Figure 11 represents the algae layer that is positioned at 250 μm wide and the relative oxygen concentration of algae layer being positioned at 500 μm wide.This figure represents algae layer, and wherein: (a) 0 μm limits the surface of the algae layer be disposed adjacent with described light source, and (b) 250 μm or 500 μm limit the surface from described light source each algae layer farthest.Typically, due to the contiguous described light source of algae, thus all the highest at 0 μm of oxygen concentration in arbitrary algae layer.

With reference to Figure 10,11 and 12, it is that the chart of the parameter of the simulation of the calculating of Oxygen Generator represents according to application more of the present invention.As described in above with reference to Figure 10, the algae on the surface of the layer of 250 μm that are exposed to described air gap wide receives enough light to produce oxygen.This oxygen diffuses in described air gap immediately.In addition, the algae layer that the algae layer passing through 250 μm wide at the oxygen of the algae layer generation of 0 μm compares by 500 μm wide spreads relatively short distance.Therefore, as shown in Figure 11, the oxygen concentration (namely ~ 17 μm) in the algae layer depth place of 250 μm wide is lower than the oxygen concentration (namely ~ 48 μm) in the algae layer depth place of 500 μm wide.The algae layer of described 250 μm wide promotes that oxygen molecule is by its high diffusivity, thus: (a) reduces described algae layer (the particularly algae of contiguous light source 1028, such as, algae in surface 1262 and 1264) in oxygen toxicity, and (b) makes more oxygen molecule diffuse in air gap 1040.

Figure 12 shows the oxygen flux of each algae layer.As illustrated, the algae layer of 250 μm wide and 500 μm wide all produces substantially equal oxygen flux (i.e. 34pMoles/ (s*cm2)) by their exposed surface.In addition with reference to the information of Figure 10 and 11, the oxygen flux that the algae layer of described 250 μm wide provides is substantially equal to the oxygen flux of the algae layer of described 500 μm wide, because: the distance that the width of the algae layer of (1) 250 μm wide makes oxygen spread to described air gap is shorter, this reduces the oxygen concentration in this algae layer, and the distance that the algae layer width of (2) 500 μm wide makes oxygen be spread by this algae layer is longer, this makes oxygen be retained in this algae layer effectively.Therefore, air gap in device 1020 promotes to described functional cell oxygen supply, reduce always take up room (the overall footprint) of this device simultaneously, for excessive oxygen molecule provides bin, and be convenient to more effectively utilize the algae in whole layer.

Oxygen Generator 1022 for wherein device 1020 only comprises the application of a photosynthetic oxygen supply 1024, and the effect of air gap 1040 is for excessive oxygen molecule provides oxygen bin, and is convenient to more effectively utilize the algae in whole layer.

For some application, support 1030 is set to comprise mineral and/or other materials (such as potassium nitrate, sodium chloride, sodium phosphate and/or magnesium compound), regulates the humidity level in shell 1060 thus.Realize this by the osmotic pressure controlling the water vapour in air gap 1040 to regulate.Typically, when osmotic pressure rising exceeds threshold quantity, water vapour condensation.In order to ensure the relative humidity level in shell 1060 lower than 100%, the mineral concentration of each support 1030 is determined, with the water vapour making described mineral when in the implanted described subject's body of shell 1060 can absorb condensation in air gap 1040 fully in the process of producing support 1030.Then, by reducing the humidity level in shell 1060, the mineral being arranged in support 1030 reduces the osmotic pressure of shell 1060.Select the mineral concentration in support 1030 to make the water of described mineral just in time enough absorption condensations; thus: (a) reduces the humidity level in shell 1060; and (b) makes osmotic pressure normalization be absorbed into (outside from shell 1060) in shell 1060 to prevent liquid, otherwise described mineral produces low-permeability environments by absorbing excessive water in shell 1060.In support 1030 the abundant absorption condensation of the mineral of debita spissitudo water vapour and do not undermine the growth conditions of algae, make the humidity level in algae layer 1026 keep constant thus.

In some applications, in order to prevent described algae from becoming dry, light source 1028 is 0.1mm and 2.0mm from the distance of algae layer 1026.In this type of application, light source 1028 produces light a long way off, and is conducted to described algae layer by illumination plate, optically-transparent tube or fiber optics.

In some applications, support 1030 comprises the material that structure is used for little by little disengaging described mineral within a period of time.In this type of application, described material contributes to regulating the mineral level in special time shell 1060, and contributes to preventing described algae from becoming dry (without regulating the effect occurring the mineral of high concentration continuously).In addition, described algae typically consumes the described mineral of part, regulates the osmotic pressure in shell 1060 thus.Therefore, by specific interval, the material discharging described mineral provides the mineral of renewal to supplement when mineral deficiency to support 1030.In some applications, by not examined to shell 1060 in the open loop type controller of parameter influence control described material released mineral matter.In some applications, described material released mineral matter is controlled by closed loop controller such as PID controller.In this type of application, support 1030 comprises the sensor constructing the parameter such as osmotic pressure and/or the condensation/humidity that are used in detection shell 1060.Then, when described sensor detects humidity and/or osmotic pressure level raises, in response to the signal that described sensor produces, described controller impels described material released mineral matter.

Referring again to Fig. 9, it is the schematic diagram of Oxygen Generator 1022 relative to the position of shell 1060.Typically, shell 1060 is shaped to provide top 1062 and the bottom 1064 of shell 1060.Top 1062 and bottom 1064 respectively comprise the first and second respective functional cell layers 1070 and 1074.Before shell 1060 is implanted in described subject's body, shell 1060 is mounted with Oxygen Generator 1022, and Oxygen Generator 1022 is between the first and second functional cell layers 1070 and 1074.The top 1062 of shell 1060 and bottom 1064 are alignd with around Oxygen Generator 1022 at least in part.In the groove of O-shape ring 1066 between 1062 parts and 1064 parts, then top 1062 and bottom 1064 are sealed.The mechanical pressure of the interface that O-shape ring 1066 is used as between 1062 parts and 1064 parts seals.Typically, the function of O-shape ring 1066 be keep pressure in shell 1060 and anti-block from shell 1060 internal leakage.

Shell 1060 comprises the electric channel (electricalchannel) 1068 shell 1060 being connected to remote circuit (not shown).Typically, near the inherent shell 1060 of the implanted described subject's body of described power supply.Alternatively, it is outside that described power supply is positioned at described subject's body, and such as, on clothing such as belt, and described power supply is transdermally connected to shell 1060 by path 10 68.Path 10 68 comprises electric wire 1069, and each electric wire 1069 is powered to each light source 1028 of Oxygen Generator 1022.

Sizing oxygen supply shell 1034 is to provide at least one ventilated membrane 1050 being configured to make oxygen be spread to functional cell layer 1070 and 1074 by it.Each ventilated membrane 1050 is typically between Oxygen Generator 1022 and functional cell layer 1070 and 1074.The shape of each ventilated membrane 1050 is typically defined as: (a) width W 1 is 5 μm-1000 μm, such as 10 μm-100 μm, and (b) diameter is 1cm-25cm, such as 3.5cm.Ventilated membrane 1050 is separated from the first and second respective functional cell layers 1070 and 1074 with the distance D2 limited by air gap 1040.Distance D2 typically is about 1 μm of-Yue 1000 μm, such as 200-500 μm (such as 300 μm).Ventilated membrane 1050 such as, is separated from algae layer 1026 by air gap 1040 (have space D 1 and be about 6mm for about 0.1mm-, 0.5mm) then.As described above, in each air gap 1040 of gas between each layer of shell 1060.

Shell 1060 typically comprises the film 1071 of the biocompatibility of selective penetrated property, for encapsulating whole shell or part enclosure (such as, as illustrated, at least covering cellular layer 1070 and 1074).Film 1071 comprises the first film 1072 be disposed adjacent with cellular layer 1070, and comprises the second film 1076 be disposed adjacent with cellular layer 1074.The feature of film 1071 is typically molecular cut off about 11,000-100,000 dalton, and this is applicable to cell generation or the nutrient consumed and material (such as oxygen, carbon dioxide, glucose, insulin or water) and can transports.The film 1071 of shell 1060 is typically also by stoping the cell (such as leukocyte) of subject's body to carry out the described functional cell of immune isolation by its transhipment.

In addition, because liquid medium typically promotes cell movement, so be arranged in the gas also immune shielding system 1020 of each air gap 1040 of shell 1060.

With reference to Figure 13, it is according to application more of the present invention, the schematic diagram of the flowing of oxygen in shell 1060.The arrow of Figure 13 represents the flowing of oxygen when it spreads from Oxygen Generator 1022 to functional cell layer 1070 and 1074.Because each algae layer 1026 contacts with the air gap 1040 of air inclusion, so the oxygen molecule produced in layer 1026 diffuses in air gap 1040.Oxygen spreads by path 10 32 and stores in different air gaps 1040, until described oxygen spreads to functional cell layer 1070 and 1074 eventually through each ventilated membrane 1050.It should be noted that exemplarily unrestricted, be depicted as use three layers of oxygen supply 1024, but scope of the present invention comprises the application of the oxygen supply 1024 wherein using such as 1 layer, 1-10 layer.

With reference to Figure 14, it is the schematic diagram of system 1020, according to application more of the present invention, it comprises containing two-layer oxygen supply 1024 (when Figure 14, it is oxygen supply 1241 and 1242) Oxygen Generator 1022, and multiple air gaps 1043 between algae layer 1026 and light source 1028.Algae layer 1026 comprises the algae being positioned at each ventilated membrane.Support 1034 comprises support, and it is convenient to form spatial relationship suitable between the algae layer 1026 of film and light source 1028.

As illustrated, for each oxygen supply 1024, algae layer 1026 is connected to support 1034, and wherein air gap 1043 is between each algae layer 1026 and light source 1028.In this type of application:

(1) each air gap 1041 is adjacent to arrange with each upper surface 1261 and 1263 of algae layer 1026.Such as, air gap 1041 and (a) are exposed to the surface 1261 of the algae layer 1026 of the keeping device 1241 of air gap 1041, and surface 1263 fluid being exposed to the algae layer 1026 of the oxygen supply 1242 of identical air gap 1041 with (b) is communicated with; And

(2) each air gap 1043 is between each algae layer 1026 and light source 1028.Such as, each air gap 1043 is between each lower surface 1262 and 1264 and light source 1028 of algae layer 1026.

Air gap 1041 and 1043 enables oxygen spread from layer 1026 and diffuse into shell by two surfaces (i.e. the surface 1261 and 1263 away from light source of each layer 1026 and the surface 1262 and 1264 of contiguous light source) of layer 1026, increases the diffusion of oxygen from algae layer thus.Algae produces maximum oxygen in the vicinity (i.e. the surface 1262 and 1264 of contiguous light source) from the nearest layer of described light source.Oxygen from described vicinity can be diffused in air gap 1043 by the surface 1262 and 1264 of contiguous light source, and need not first be spread by algae layer 1026, is then diffused out to air gap 1041 by the surface 1261 and 1263 away from light source.

Scope of the present invention should be understood and comprise cell for the transplanting except islet cells, such as, the cell oxygenation of the transplanting described in document of quoting in the background technology part of present patent application.For some application, utilization is connected with shell 1060 or strengthens the vascularization around shell 1060 at one or more Some Circulating Factors (such as VEGF) that shell 1060 is contiguous.

It should be noted that scope of the present invention comprises the purposes of the device 1020 independent of functional cell layer 1070 and 1074.In this type of application, device 1020 is used as Oxygen Generator, and comprises the outlet (this application is not shown) being configured to discharge the oxygen produced.In some applications, such device can in the body of implanted described object.

Scope of the present invention comprises following patent and the application described in patent application (they are incorporated to herein by quoting).In application more of the present invention, the technology and equipment described in one or more following patent and patent application and the techniques described herein and equipment are combined:

● the open WO 01/050983 of PCT patent, is filed in January 12 calendar year 2001, is entitled as " Implantable device ";

● U.S. Patent application 10/466,069, is filed on March 12nd, 2004, is entitled as " Implantable device ";

● U.S. Patent Application Publication 2005/0136092, is filed in November 30 in 2004, is entitled as " Implantable device ";

● the open WO 06/059322 of PCT patent, is filed on November 27th, 2005, is entitled as " Implantable device ";

● U.S. Provisional Patent Application 60/860,632, is filed on November 22nd, 2006, is entitled as " Protecting algae from body fluids ";

● U.S. Provisional Patent Application 60/861,592, is filed on November 28th, 2006, is entitled as " Oxygen supply for cell transplant andvascularization ";

● the open WO 08/065660 of PCT, is filed on November 28th, 2007, is entitled as " Oxygen supply for cell transplant and vascularization ";

● U.S. Provisional Patent Application 60/993,052, is filed in JIUYUE in 2007 7, is entitled as " Air gap for supporting cells ";

● the open WO 08/062417 of PCT, is filed on November 22nd, 2007, is entitled as " Protecting algae from body fluids ";

● U.S. Patent application 12/064,946, is filed on February 26th, 2008, is entitled as " Oxygen supply for cell transplant and vascularization ";

● the open WO 09/031154 of PCT, is filed in JIUYUE in 2008 7, is entitled as " Air gap for supporting cells "; And/or

● U.S. Provisional Patent Application 61/192,412, is filed in JIUYUE in 2008 17, is entitled as " Optimization of alginate encapsulation of islets fortransplantation ".

Scope of the present invention comprises the embodiment described in U.S. Provisional Patent Application (it is transferred the assignee in present patent application and is incorporated to herein by quoting) being entitled as " Protecting algae from body fluids " being filed on November 22nd, 2006 of the people such as Rotem.For some application, the technology described in this temporary patent application and the techniques described herein combine to be implemented.

For some application, the technical combinations described in one or more documents quoted in the background technology part of the techniques described herein and present patent application is implemented.

It will be understood by those skilled in the art that the invention is not restricted to above specifically shown in and described those.Scope of the present invention comprises combination and the sub-portfolio of various features mentioned above, also comprises those skilled in the art's also non-existent change and amendment in this area that can expect when reading above-mentioned description.

Claims

1., for the equipment to transplanted cells transport oxygen, it comprises:

Graft, it comprises:

Shell, it is configured to implant in subject, and described shell of shaping is with the oxygen bin providing structure to be used for storing gaseous oxygen;

Functional cell, it is connected with described shell, and is communicated with described oxygen bin;

The one or more oxygen arranged away from described shell send opening, and described one or more oxygen of shaping sends each in opening, and to provide corresponding oxygen to send interface, described oxygen is sent interface and had the upper surface comprising transparent surface;

Corresponding one or more pipe, connect described one or more oxygen and send opening and described shell, and structure is to promote oxygen to send from described one or more oxygen the bin that opening is transported to shell, the respective openings that in described one or more pipe, each is sent in opening at its first end and described one or more oxygen is connected, and be connected with described shell at its second end

Oxygen source, its structure installation is outside at the health of object, and structure is to send opening and corresponding one or more pipe to described functional cell supply oxygen by described one or more oxygen; With

Pin, it is configured to transdermal and pierces through transparent surface that described one or more oxygen sends opening,

Wherein:

Described shell can be connected with described oxygen source indirectly,

Construct described pin to promote from described oxygen source to described cell oxygen supply,

Described oxygen sends interface, and its structure is used for receiving oxygen by described pin from described oxygen source, and is used for promoting to described functional cell transhipment oxygen, and described shell is positioned at the body of described object, and

By described pin, described oxygen source is sent opening with described shell, described one or more oxygen to be connected with described one or more pipe,

By described pin described oxygen source sent opening with described shell, described one or more oxygen and described one or more pipe is connected,

2. equipment as claimed in claim 1, wherein said functional cell comprises the cell being arranged in islets of langerhans.

3. equipment as claimed in claim 1, described oxygen source comprises multiple gases.

4. equipment as claimed in claim 1, wherein said oxygen source comprises the oxygen carrier of preoxygenation.

5. equipment as claimed in claim 1, wherein said oxygen is sent interface and is reversibly connected with described oxygen source.

6. equipment as claimed in claim 1, wherein constructing described shell is enough at the 12 little oxygen-containing gas amounts maintaining described functional cell within the time of 2 weeks to provide.

7. equipment as claimed in claim 1, wherein shape described shell with provide stretch into described object tissue in multiple thrusts, described thrust structure is used for absorbing oxygen from the vascular system of described object.

8. the equipment according to any one of claim 1-7, wherein said functional cell is arranged at least one hydrogel layer, and described hydrogel layer structure is used for the health of the immunity described cell of isolation and described object.

9. equipment as claimed in claim 8, wherein said functional cell is arranged at least the first and second hydrogel layers, and described first and second hydrogel layers are positioned at the either side of described oxygen bin.

10. equipment as claimed in claim 9, the size of wherein said oxygen bin is the longest, than being provided with, size the longest in the first and second hydrogel layers of described functional cell is longer, and wherein said oxygen bin is provided for the surf zone absorbing oxygen from the peripheral vascular system of described object.

11. equipment as claimed in claim 9, described oxygen bin of wherein shaping is to provide series of passages, and described passage is convenient to the orientation transhipment of fluid in described oxygen bin.

12. equipment as claimed in claim 11, wherein said oxygen bin comprises at least one valve, and described valve constitution is used for being convenient to the orientation transhipment of fluid in described oxygen bin.

13. equipment as claimed in claim 9, wherein construct described shell with near the thoracic cavity of implanting described object, and wherein construct described shell with the motion in the thoracic cavity along with described object, described shell response motion, thus oxygen is circulated in described bin.

14. equipment as claimed in claim 13, wherein said oxygen bin comprises hydrogel, and described hydrogel is finalized to define the passage that structure is used for being convenient to the orientation transhipment of oxygen in described bin.

15. equipment as claimed in claim 1, wherein said oxygen bin structure is used for the storing fluids at pressures at least 1atm.

16. equipment as claimed in claim 1, the volume of wherein said oxygen bin is 100ml-300ml.

17. equipment as claimed in claim 1, wherein said oxygen bin air inclusion.

18. equipment as claimed in claim 1, wherein said oxygen bin comprises structure and is used for the oxygen carrier of the excess of oxygen absorbed in described oxygen bin.

19. equipment as claimed in claim 1, it also comprises the ventilated membrane between described bin and described functional cell.

20. equipment as claimed in claim 1, described pin of wherein shaping is to limit at least one room, and wherein said pin can be connected with described oxygen source, and is configured to transdermal and pierces through transparent surface that described oxygen sends the upper surface at interface.

21. equipment as claimed in claim 20, at least one room wherein said structure is used for being convenient to send oxygen from described oxygen source to the described functional cell be connected with described shell.

22. equipment as claimed in claim 20, wherein:

At least one room described comprises the first Room and the second Room,

23. equipment as claimed in claim 22, wherein said second Room structure is used for being convenient to described fluid from passive transport in described shell, and by described first Room to described shell oxygen supply.